Comparison of SHOX and associated elements duplications distribution between patients (Lėri-Weill dyschondrosteosis/idiopathic short stature) and population sample

Hirschfeldova, Katerina; Šolc, Roman

doi:10.1016/j.gene.2017.06.034

Cited by 12 publications

(15 citation statements)

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“…Point mutations or deletions resulting in haploinsufficiency of SHOX are also associated with idiopathic growth retardation,27 and idiopathic short stature (ISS) and are causative of Leri–Weill dyschondrosteosis (LWD), a dominant skeletal dysplasia presenting with mesomelic limb shortening and curving of the radius known as Madelung deformity 28 29. Homozygous loss of SHOX or compound heterozygous SHOX defects result in the more severe phenotype known as Langer mesomelic dysplasia (LMD) 23 30–32. Mesomelic involvement of the lower legs observed in patients with LWD and LMD with SHOX defects is consistent with the predominant anatomic abnormalities previously described in patients with idiopathic clubfoot, in which skeletal muscle hypoplasia is most evident in the lower legs but not the calf 33…”

Section: Discussionmentioning

confidence: 99%

Rare andde novoduplications containingSHOXin clubfoot

et al. 2020

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IntroductionCongenital clubfoot is a common birth defect that affects at least 0.1% of all births. Nearly 25% cases are familial and the remaining are sporadic in inheritance. Copy number variants (CNVs) involving transcriptional regulators of limb development, including PITX1 and TBX4, have previously been shown to cause familial clubfoot, but much of the heritability remains unexplained.MethodsExome sequence data from 816 unrelated clubfoot cases and 2645 in-house controls were analysed using coverage data to identify rare CNVs. The precise size and location of duplications were then determined using high-density Affymetrix Cytoscan chromosomal microarray (CMA). Segregation in families and de novo status were determined using qantitative PCR.ResultsChromosome Xp22.33 duplications involving SHOX were identified in 1.1% of cases (9/816) compared with 0.07% of in-house controls (2/2645) (p=7.98×10−5, OR=14.57) and 0.27% (38/13592) of Atherosclerosis Risk in Communities/the Wellcome Trust Case Control Consortium 2 controls (p=0.001, OR=3.97). CMA validation confirmed an overlapping 180.28 kb duplicated region that included SHOX exons as well as downstream non-coding regions. In four of six sporadic cases where DNA was available for unaffected parents, the duplication was de novo. The probability of four de novo mutations in SHOX by chance in a cohort of 450 sporadic clubfoot cases is 5.4×10–10.ConclusionsMicroduplications of the pseudoautosomal chromosome Xp22.33 region (PAR1) containing SHOX and downstream enhancer elements occur in ~1% of patients with clubfoot. SHOX and regulatory regions have previously been implicated in skeletal dysplasia as well as idiopathic short stature, but have not yet been reported in clubfoot. SHOX duplications likely contribute to clubfoot pathogenesis by altering early limb development.

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Section: Discussionmentioning

confidence: 99%

Rare andde novoduplications containingSHOXin clubfoot

et al. 2020

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“…Studying LWD and ISS patients identified that duplications in SHOX and its associated elements are less frequent than deletions of SHOX. SHOX-associated elements are conserved non-coding elements (CNE) adjacent to the 3′ end (CNE-3,4,5,7,8,9) and 5′ end (CNE-2,3,5) of the gene [4,7]. Previous studies have investigated the frequency and distribution of duplications within SHOX and its associated elements between population samples and merged groups of ISS/ LWD patients [7].…”

Section: Discussionmentioning

confidence: 99%

“…SHOX-associated elements are conserved non-coding elements (CNE) adjacent to the 3′ end (CNE-3,4,5,7,8,9) and 5′ end (CNE-2,3,5) of the gene [4,7]. Previous studies have investigated the frequency and distribution of duplications within SHOX and its associated elements between population samples and merged groups of ISS/ LWD patients [7]. This group proposed that partial SHOX duplications and small duplications encompassing the CNE-9 enhancer could be highly penetrant alleles associated with ISS and LWD development.…”

Section: Discussionmentioning

confidence: 99%

“…The findings in this study suggest that duplications of upstream and downstream long-range cis-regulatory DNA elements can result in a SHOX-related phenotype. Controversially, Hirschfeldova and Solc described this duplication area only as a polymorphism, as they detected it in their population sample (0.40%) and in only one case from their LWD/ISS samples (0.28%) [7]. The precise mechanisms of the pathogenic effects of microduplications are not yet understood.…”

Section: Discussionmentioning

confidence: 99%

“…Partial or complete SHOX duplications, ranging from 13 to 346 kb, have been reported in patients with SS. Such defects are thought to result in decreased SHOX expression due to disruption of the interaction between its enhancer regions and promoter [2,[4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Screening of the SHOX/PAR1 region using MLPA and miRNA expression profiling in a group of Egyptian children with non-syndromic short stature

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Abdelrahman

et al. 2020

Egypt J Med Hum Genet

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Background Short stature is defined as a body height below the third percentile, based on chronological age, or 2 standard deviations (SD) below the national height standard. The prevalence of short stature is around 2% of children worldwide. Several gene deficiencies have been associated with the etiology of short stature. The SHOX is an important candidate gene for short stature, as its haploinsufficiency underlies syndromic and non-syndromic short stature. Partial and complete duplications of SHOX have been reported in patients with short stature. Proper genetic diagnosis of these children allows for appropriate therapeutic approaches to be administered. Since copy number variation (CNV) is a possible mechanism of interhuman variability and pathogenic disease, the multiplex ligation-dependent probe amplification technique (MLPA) can be used as an initial screening technique. Cartilage tissue expresses specific microRNAs (miRNAs), which play an essential role in the regulation of chondrocyte proliferation and differentiation during growth plate development. We aimed to assess the SHOX/PAR1 region using CNV profiling for non-syndromic short stature in Egyptian children with and without growth hormone deficiency using the MLPA technique and expression profiling of miR-1, miR-15a, and miR-140 using quantitative real-time polymerase chain reaction (qRT-PCR) in a group of Egyptian children with non-syndromic short stature. Results Of the fifty cases included in this study, different CNVs were detected in ten children (20%), in/outside the SHOX region. Moreover, in children with short stature, the expression level of miRNA-140 was significantly different from that of healthy controls. Conclusions This is one of the first studies that have assessed CNVs in the SHOX/PAR1 region in a group of Egyptian children with short stature. MLPA analysis of SHOX/PAR1 identified different CNVs in children with non-syndromic short stature, suggesting that the MLPA should be used as an initial screening technique in short children, as proper genetic diagnosis of these children leads to implementation of the appropriate therapeutic approach. Alterations in the levels of miRNA-140 in children with short stature suggest that changes in the expression levels of this miRNA are associated with the pathogenesis of short stature.

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